Epstein-Barr virus infections of the nervous system
Nov. 11, 2023
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CNS listeriosis is a rare but very important disease, as it has the second highest case fatality rate amongst food borne diseases. Almost one third of all patients die despite adequate therapy, and hardly one third survive unscathed.
Listeria monocytogenes is a very unusual bacillus, dreaded by the food processing industry as this ubiquitous, harmless saprophyte and is able to survive for years, and suddenly in a Jekyll-like manner, transform into a dangerous pathogen targeting infants and elderly, or sick and immunocompromised persons, with a particular affinity for the brain, causing meningitis, meningoencephalitis, or abscesses.
This fascinating bacillus has evolved to survive adverse environments, biding time for years in a dormant form, inhibiting other competitive organisms in soil and the gut. When conditions are right it can awaken, multiply rapidly, and silently invade a host, hiding and spreading from cell to cell within the intracellular space, evading the immune system and antibiotics. It hijacks various host processes and puts them to work for its benefit.
Almost like a science fiction story, it can travel backwards from the gut and oral mucosa inside the vagus and trigeminal nerves directly to the brainstem.
Systemic or invasive listerial infections mainly afflict persons with a predisposing conditions, including pregnancy, glucocorticoid therapy, other immunocompromising conditions, and extremes of age. Yet, one must always keep in mind, the rare variety of Listeria rhombencephalitis, causing a deceptively benign looking acute brainstem disorder in healthy young adults. If missed, infection may progress within a few days to bulbar palsy, respiratory paralysis, and even death.
Similarly, pregnant women need to know they are at high risk and consider that what looks like a simple urinary infection or flu-like illness may lead to the loss of their baby.
Only certain older antibiotics like ampicillin or penicillin, gentamicin, or trimethoprim-sulfamethoxazole work against it, better than meropenem, whereas third generation cephalosporins actually fail.
We can ignore Listeria only at our peril.
• Listeriosis is a rare disease, but it is important because it has the second highest case-fatality rate amongst food borne diseases.
• Almost one third with CNS infection die, and hardly one third escape without any major disability.
• This gram positive rod is the bane of the food industry in various ways.
• Risky foods include dairy products, fruits and vegetables, meat products, and fish products; it is even in hospital foods.
• Everyone, but more so persons at high risk, need to be educated about food choices and food handling.
• Many get exposed, but infants, elderly, or persons with impaired immunity are at risk for invasion of the bloodstream or the brain.
• Listeria has the unique ability to silently evade various defense mechanisms, cross barriers, and move intracellularly and within axons.
• Rhombencephalitis is a deceptive but extremely dangerous form of listeriosis, often seen in healthy and young persons.
• Pregnant women are very prone to get listeriosis and may present with an innocuous flu-like illness. It is very important to recognize and treat, as otherwise the baby can become seriously ill.
• A high index of suspicion and early treatment are the key to success as even a few hours of delay may lead to death.
• The therapy of choice for CNS listeriosis is ampicillin or benzylpenicillin combined with an aminoglycoside or TMP-SMX, with meropenem plus gentamicin only as the third alternative.
• The duration of therapy in CNS listeriosis should be at least 3 to 4 weeks in immunocompetent and 6 to 8 weeks in immunosuppressed persons.
• Steroids are probably deleterious and should not be used in CNS listeriosis.
Listeria monocytogenes has long been recognized as a veterinary pathogen causing basilar meningitis and stillbirth in sheep and cattle. It was first described as human pathogen in a patient with a mononucleosis-like syndrome in 1929 (85).
Meningitis due to L monocytogenes was described in 1936, but the first authentic isolation came from a World War I soldier in 1918. His meningitis was attributed to a diphtheroid species. However, the original culture was preserved at the Pasteur Institute in Paris and was identified 20 years later as L monocytogenes. This historical note provides an important reminder that L monocytogenes is sometimes confused and dismissed as a diphtheroid contaminant because of morphological, colonial, and biochemical similarities. A 1949 German epidemic of “granulomatosis infantisepticum” led to the discovery that L monocytogenes caused this severe neonatal infection (47). Brainstem encephalitis or rhombencephalitis due to Listeria was first described in 1957 (37). The first foodborne outbreak of listeriosis was attributed to infected vegetables in a Boston Hospital in 1979 (41).
This gram-positive bacterium has been known by many names, including Listerella hepatolytica, Corynebacterium infantisepticum, Corynebacterium parvulum, and Erysipelothrix monocytogenes. In 1940 taxonomists reached a general agreement to call the species Listeria monocytogenes in honor of the father of antisepsis, Lord Lister (100).
• Listeriosis primarily affects pregnant women, newborns, older adults, and people with weakened immune systems.
• In healthy persons, Listeria usually causes a self-limited gastroenteritis.
• A small percentage (4%) of otherwise healthy and young persons can get CNS Listeriosis.
• Rhombencephalitis is a deceptive but extremely dangerous brainstem infection, typically seen in healthy and young persons.
• In pregnant women, Listeria bacteremia usually is mild and mimics a simple urinary infection or a “flu.” It may lead to spontaneous abortion or neonatal sepsis, but early antimicrobial therapy may allow the birth of a healthy child.
• In the immunocompromised, Listeria evolves to a deadly form of invasive disease in the form of bacteremia, CNS invasion, or various focal infections. Listeria has a predilection for the brain, and so it is uncommon to have pure meningitis without brain involvement.
• CNS listeriosis can cause anything from a mild fever with some mental change to frank coma.
• Almost all have fever, headache is seen in the majority, but neck stiffness may be absent.
• Keeping a high index of suspicion and instituting early treatment are key to success.
• Despite treatment, CNS listeriosis has a very high morbidity and mortality.
Listeria gastroenteritis. This form of listeria mainly occurs in healthy and immunocompetent children and adults and tends to cause a self-limited gastroenteritis with diarrhea, fever, and body aches. It typically occurs within 24 hours of ingesting a large number of bacteria in contaminated food; it is self-limited with recovery within a couple of days due to a robust immune response. Culture proof is difficult to obtain; therefore, diagnosis is usually presumptive in a person with gastroenteritis soon after exposure in a known Listeria outbreak (70; 40).
Invasive listeriosis can take the form of bacteremia, with subsequent CNS or various focal infections, including peritonitis, cholecystitis, hepatitis, pleuritis, splenic abscesses, pericarditis, osteomyelitis, endophthalmitis, and others. Most cases of invasive disease occur in the immunocompromised or elderly or pregnant women. The average incubation period is 10 days (range: 0 to 21 days) (03).
Invasive disease takes a milder form of bacteremia in pregnant women, where it is much less likely to invade the CNS.
Listeria Bacteremia. It looks like any other bacteremia, except in pregnant women, where it looks like a simple urinary tract infection or a “flu” (82). The MONALISA study of 427 cases found 94% of patients presented with fever, and the C-reactive protein was elevated in 96%. Signs and symptoms are nonspecific like any other bacteremia. Patients may report an antecedent diarrheal illness or nausea (24).
CNS Listeriosis. L monocytogenes can cause meningoencephalitis, meningitis, cerebritis, abscess, and brainstem infection with the clinical status varying from a mild fever with minor mental changes to frank coma (81).
Unlike the other common pathogens that cause bacterial meningitis, L monocytogenes has a proclivity to the brain itself (69). Pure meningitis is less common than meningoencephalitis, 13% versus 84% (24).
Fever is seen in 91% to 100% of CNS listeriosis patients regardless of immune status. Headache is present in three quarters of patients with CNS disease and obviously is a nonspecific symptom (09). Between 25% to 42% patients may not show signs of meningeal irritation (81; 24; 06).
Meningoencephalitis. This is the commonest type of CNS listeriosis and is seen in 84% of cases (212 out of 252). Fever is seen in almost all, neck stiffness in 163 out of 252 cases (65%), seizures in 46 out of 252 (18%), and a limb paresis in 31 out of 252 (12%). Headache is very common (24).
In another series of 100 cases, headache (97%), fever (96%), and neck stiffness (75%) were detected in most cases, and 70% had altered consciousness. The classical triad of fever, neck stiffness, and altered level of consciousness was seen in 50%. Focal signs and seizures were each seen in 30%. Nineteen percent of patients had at least one cranial nerve paralysis, and 5% had multiple cranial nerve paralyses. Involvement of the sixth and seventh cranial nerves was the most common, in 9% each (07). Another review of 82 cases found nearly half of all cases had some cranial nerve palsy at admission, with facial nerve palsy in 37% (06).
Meningitis. A meningitis-like presentation without encephalitic features is seen in only 13% to 15% cases (24; 06).
The onset may not be abrupt as seen with pneumococcal or meningococcal meningitis, and neck stiffness may even be absent in up to 20%. In the elderly, neck stiffness, headache, or fever may be absent in up to 40%, and they may present only with altered consciousness (89). Thus, absence of meningeal signs does not rule out Listeria meningitis or meningoencephalitis.
Rhombencephalitis. L monocytogenes can cause a brainstem encephalitis, called rhombencephalitis involving the pons and medulla. It is probably underrecognized but reported in 9% to 17% cases of CNS listeriosis (09; 24). Peculiarly this is the main form of CNS listeriosis in ruminant animals like cattle or sheep, causing unilateral hemiparesis or ataxia, causing the animal to walk in circles, which is called “circling disease.”
In contrast to the other forms, rhombencephalitis tends to strike healthy adults, ranging from 70% to 92% (05; 57).
Listeria rhombencephalitis often has a very characteristic biphasic presentation, with an initial deceptively benign looking phase, which if missed, may rapidly progress to life-threatening illness.
The initial clinical manifestations are nonspecific, such as malaise, fever, headache, vomiting, and sweating. Early recognition in this prodromal stage of 4 to 15 days is challenging (87; 106). Meningeal signs and fever may be absent in 15% cases; therefore, one may not think of a life-threatening brain infection (09; 99). At this stage, diagnosis can be difficult and missed even after CSF examination and MRI.
If missed, the next stage sets in rapidly with progressive brainstem deficits, including asymmetric cranial nerve palsies (facial paresis, diplopia, dysphagia, palatal palsy, dysarthria, and paresthesias in the trigeminal region), as well as long tract signs in the form of cerebellar ataxia, motor and/or sensory deficits in the limbs (hemiparesis or tetraparesis, spasticity, or increased tendon reflexes), and impaired consciousness, including coma and seizures. Almost one half develop respiratory failure (106; 09; 87).
In a review of 123 cases, fever was seen in the majority (82.7%) at onset, and most (74%) had prodromal symptoms, but less than half (44.3%) showed meningeal symptoms (57). The other symptoms were as follows: an eye movement disorder in 2 out of 3; headache, altered mental status, or limb ataxia in one in 3; nausea/vomiting and nuchal rigidity in one in 4; and dysarthria, dizziness/vertigo, or dysphagia in one out of 5. The age of patients ranged from 14 to 87 years, with 16 patients less than or equal to 29 years of age.
Listerial rhombencephalitis has been reported to cause a fairly sudden hemiparesis, mimicking a stroke (71).
Cerebritis and abscess. Unlike other bacteria, listerial brain abscess coexists with bacteremia in nearly all cases and with meningitis in one fourth; in addition, abscesses are often subcortical (24).
Spinal cord abscess has also been reported (59; 96), and acute cervical myelitis from L monocytogenes was described in immunocompetent patients (84; 55).
Neonatal meningitis. Neonatal listerial infection is usually divided into 2 types: early onset and late onset.
Early-onset infections usually present as a generalized sepsis that develops within the first or second day of life. They are associated with prematurity and a preceding maternal illness. Consequently, they are thought to be the result of intrauterine infection. A severe disseminated form of infection, granulomatosis infantisepticum, frequently results in stillbirth or death within hours. Disseminated abscesses are seen in these neonates. Generalized maculopapular rash and hepatomegaly may be seen in early-onset neonatal listeriosis as well (11).
Late-onset neonatal listeriosis presents as a meningitis in 94% (15). It looks clinically like other meningitis but tends to occur after the first week of life, unlike group B Streptococcus and E coli, which are more likely to occur within the first week following birth. The most frequent presenting manifestations of neonatal listerial meningitis are fever (96%), irritability (72%), and anorexia (40%) (111).
Nonneurologic syndromes. L monocytogenes can cause several nonneurologic syndromes, including cutaneous and conjunctival listeriosis in veterinary or lab workers; bacterial endocarditis in persons with valvular disease, hepatitis, and liver abscess; and peritonitis in persons undergoing continuous ambulatory peritoneal dialysis, biliary tract infection, osteomyelitis, and septic arthritis. Most of these infections also occur in immunocompromised persons (99).
The most common type of CNS listeriosis in nonpregnant adults is an acute meningitis or meningoencephalitis. In the United States, Listeria monocytogenes is the fifth most common pathogen isolated from patients with bacterial meningitis (3.4% of cases), after Streptococcus pneumoniae (58.0%), Group B Streptococcus (18.1%), Neisseria meningitidis (13.9%), and Haemophilus influenzae (6.7%) (104). Listerial meningitis cannot be reliably distinguished from other causes of meningitis on clinical grounds. Patients generally present with acute or subacute onset of fever, nuchal rigidity, headache, and altered mental status. In a prospective study of 30 patients, 97% had at least 2 of these 4 symptoms (17). Movement disorders such as ataxia, tremors, and myoclonus occur in 15% to 20% of cases, and 25% develop seizures (69; 81). Disturbances of mental status ranging from drowsiness to coma were observed in 77% of patients in one large series (81). Hydrocephalus can occasionally complicate listerial meningitis (58).
L monocytogenes can also cause brainstem encephalitis, which is also referred to as rhombencephalitis. The pons and medulla are involved in two thirds of patients. In a Norwegian cohort of 172 adult, nonpregnant patients with confirmed listeriosis, 19 had evidence of brainstem encephalitis (11%) (04). None of the 40 pregnant women with listerial infection had brainstem involvement in this cohort. A biphasic course has been described with an initial phase of headache, fever, nausea, and vomiting, followed by asymmetric lower cranial nerve palsies, cerebellar signs, motor or sensory dysfunction, and altered mental status. Unilateral facial nerve palsy is the first and most frequent cranial nerve palsy (78%). In contrast to other forms of listerial infection, rhombencephalitis strikes healthy adults; only about 8% are immunocompromised (05). Listerial rhombencephalitis has been reported to cause hemiparesis, which may be present as one of the only symptoms, thus mimicking stroke. About 30% of presentations of acute focal neurologic deficit can be attributed to stroke mimics, such as seizure, syncope, migraine with aura, and infection (71).
Cerebritis and abscess formation occur in about 1% of patients with listeriosis. Immunosuppression is the major risk factor. Men are more often affected than women with a ratio of 6:1. Mortality is nearly 3 times higher than nonlisterial brain abscesses (29). Spinal cord abscess has also been reported (59; 96), and acute cervical myelitis from L monocytogenes was described in immunocompetent patients (84; 55).
Approximately one third of listerial meningitis occurs in the newborn. Neonates can become infected transplacentally from maternal bacteremia. The organism can also be acquired during vaginal delivery. Neonatal listerial infection is usually divided into 2 types: early onset and late onset. Early-onset infections usually present as a generalized sepsis that develops within the first or second day of life. They are associated with prematurity and a preceding maternal illness. Consequently, they are thought to be the result of intrauterine infection. A severe disseminated form of infection, granulomatosis infantisepticum, frequently results in stillbirth or death within hours. Disseminated abscesses are seen in these neonates. Generalized maculopapular rash and hepatomegaly may be seen in early-onset neonatal listeriosis as well (11). Late-onset neonatal listeriosis presents after 7 days of life. Meningitis is present in 94% of late-onset cases (15). Clinical features do not distinguish neonatal listerial meningitis from other causes of meningitis. However, unlike listerial meningitis, meningitis due to group B Streptococcus and E coli is more likely to occur within the first week following birth. The most frequent presenting manifestations of neonatal listerial meningitis are fever (96%), irritability (72%), and anorexia (40%) (111). Infection rarely occurs in infants or children after the first months of life.
L monocytogenes can cause several nonneurologic syndromes. A generalized listerial bacteremia can present as fever, myalgias, malaise, and backache. Individuals who ingest a significant amount of the organism can develop a self-limited febrile gastroenteritis (70). Pregnant women most commonly develop infections in the third trimester that present as a nonspecific, acute febrile illness (see Pregnancy section). Infection can threaten the fetus by causing amnionitis, premature labor, or, rarely, stillbirth.
• CNS infection is almost always fatal if untreated and around 30% with treatment, going up to 50% in rhombencephalitis or brain abscesses.
• One third need artificial ventilation.
• Two thirds survive with significant neurologic disability.
• Prognosis is better in healthy individuals.
• Factors associated with mortality, include old age, ongoing malignancy, bacteremia, monocytopenia, immunocompromised status, and steroid therapy.
• Complications include focal deficits, hydrocephalus, infarcts, and seizures.
Mortality. Listeriosis is the third leading cause of death amongst foodborne illnesses with about 260 deaths per year. The case-fatality rate is about 20%.
Nearly one-quarter of pregnancy-associated cases result in fetal loss or death of the newborn. More information can be accessed at the following website:www.cdc.gov.
The MONALISA study showed the 3-month mortality was 45% in patients with bacteremia (194 of 427 patients); 30 percent in those with CNS infection (75 of 252 patients); and no deaths in 107 pregnant patients (24). Untreated CNS infection is almost universally fatal (24; 40).
Prognosis is better in those without serious underlying disease, those who are not immunocompromised, those who are not pregnant, and in younger adults (22; Rogalla and Bomar 2021). In two series of 281 and 74 patients, there were no deaths in otherwise healthy patients compared with an overall mortality rate of 22% to 32% in patients with underlying health conditions (102; 45).
Mortality in rhombencephalitis or abscess is higher, between 30% to 50% (05; 57; 99). Mortality in listerial brain abscess is nearly 3 times higher than nonlisterial brain abscesses (29).
A retrospective study of 100 cases of CNS listeriosis found that seizure and delay in treatment were most significantly associated with mortality (07).
The MONALISA study found the following factors associated with mortality: older age, female sex, ongoing malignancy, multiple organ failure, worsening of prior organ disease, weight loss, monocytopenia less than 200 cells/µL, elevated neutrophil count, bacteremia, and dexamethasone administration. Neurolisteriosis patients with encephalitis had 3 times higher mortality than those without encephalitis (33% vs. 9%) (24).
Community-acquired Listeria meningitis in an analysis of 92 cases in the Netherlands comparing those in the period 1998 to 2002 with the period 2006 to 2012, showed unfavorable outcome to have increased from 27% to 61% (61). This increase was attributed to the increase of L monocytogenes genotype sequence type 6 (ST6) jumping from 4% in the earlier period to 29% in the later period.
Morbidity. Morbidity in survivors is high, with significant residual disability in over two thirds (24; 06). Neurologic sequelae were most likely to be experienced in patients whose treatment was delayed beyond 7 days or who had L monocytogenes bacteremia (07). Long-term neurologic sequelae included limb motor deficiencies, cerebellar symptoms, and eighth nerve palsy (24).
Rhombencephalitis or abscess also had up to 61% survivors having significant residual deficit (38; 57; 99).
Although pregnant women with listeriosis generally do not have CNS involvement, systemic infection during pregnancy can lead to amnionitis, premature labor, or, rarely, stillbirth.
Complications. The course of the illness may be complicated by focal deficits, hemiparesis, quadriparesis, bulbar palsy, and need for artificial ventilation, as well as seizures, hydrocephalus, and increased intracranial pressure. Cerebral vasospasm with subsequent infarction can occur days or weeks after initial presentation (60). Almost one third need artificial ventilation (24).
A 50-year-old man developed a severe headache, lethargy, and fever over 2 days. He came to medical attention when his wife found him disoriented and combative. In the emergency room, he had a generalized seizure followed by ventricular tachycardia requiring cardioversion. His past medical history was remarkable for adult-onset diabetes mellitus, active pulmonary sarcoidosis treated with 30 mg prednisone daily, alcoholic cirrhosis, and splenectomy after a gunshot wound. Before the seizure, he was arousable only by a loud voice. He was disoriented to place. Vital signs included a temperature of 39.2°C, blood pressure of 108/70 mmHg, regular pulse of 98 per minute, and respirations of 12 per minute. He had a small liver with abdominal distention and shifting dullness. His neurologic exam exhibited meningismus, withdrawal of all 4 limbs to painful stimulus, and normal cranial nerves. Deep tendon reflexes were normal.
A noncontrast head CT scan was unremarkable. Lumbar puncture showed an opening pressure greater than 30 cm of water, cloudy fluid, 8400 white blood cells per mm3 with 90% neutrophils and 10% lymphocytes. Red blood cells were 986 per mm3. Glucose was 291 mg/dL (serum 410 mg/dL) and protein measured 291 mg/dL. The CSF Gram stain was unremarkable. Blood and CSF cultures showed growth after 2 days, and L monocytogenes was identified at day 3. The patient initially received intravenous vancomycin, ceftriaxone, and ampicillin. After bacterial identification the treatment was switched to a combination of ampicillin and gentamicin and continued for 3 weeks. Recovery was complete within 10 days.
• L monocytogenes is a gram-positive rod, with flagella giving it a peculiar tumbling motility
• Still can be mistaken for other less dangerous bacteria
• Able to survive in various environments that are adverse for most other microorganisms
• Can survive for years in food processing facilities by forming biofilms
• Competes with and inhibits other bacteria in the gut and possibly even in soil
• Like Jekyll and Hyde, can switch from a peaceful saprophyte form to a dangerous pathogenic form in mammals
• On ingestion quietly gets past the gastric epithelium and in immunosuppressed gets into the bloodstream and to the brain or to the placenta
• In immunocompetent can reach brainstem via retrograde transport in axons of certain cranial nerves
• Armed with various virulence factors like internalins and Listeriolysin, has the unique ability to silently evade various defense mechanisms, cross barriers, survive, adapt, live, and move within cells, hijacking various host processes to its own cause
• Once in the brain may spread along axons and use the good immune response to cause inflammation and progressive disease
Microbiology. Of the 17 Listeria species, only 3 are opportunistic pathogens in humans, mostly L monocytogenes, but, rarely, Listeria ivanovii, and Listeria grayi (52).
L monocytogenes is a gram positive rod with flagella or “whips,” which gives it the characteristic tumbling motility. It can sometimes seem gram-negative, and the rods may be short enough to mimic cocci; therefore, it can be mistaken for various less dangerous bacteria like diphtheroids, Enterococcus spp, S pneumoniae, H influenzae, or enteric bacteria (19). It grows well on most routine culture media and usually forms a narrow zone of β-hemolysis on blood agar (52).
There are more than 14 serotypes, which are differentiated based on their somatic (O) and flagellar (H) antigens. Most human cases are caused by the serotypes 1/2a, 1/2b, and 4b. Various PCR methods can be used to quickly identify the different serotypes. Whole-genome sequencing has been a valuable tool in outbreak tracing (16).
Listeria is a very flexible and adaptive organism, easily switching from a saprophytic mode of life in soil to one where it causes infection in animals and humans (44; 93).
It is found widely in soil, water, vegetation, and food. It is a very adaptive and flexible organism, is able to survive in aerobic or anaerobic environments, and is able to resist environmental stresses like temperatures, acidic pH, dryness (93; 99).
In the cold and harsh food-processing environment, it enjoys a competitive advantage over other microorganisms and can survive for even years, due to its ability to endure various stresses, such as sanitizers, pH, temperature, UV light, and drying (54), and by forming biofilms, or thin sticky films attached to various surfaces, thereby evading various eradication measures and disinfectants (75).
It can bide time and multiply rapidly once conditions become conducive, for example, warmer (30°C to 37°C) or more alkaline.
Like its strategy of survival in the environment, even inside the cell, it can temporarily adopt a dormant but viable vacuolar form, undetected by culture, evading the immune system and resisting antibiotics (12).
Pathobiology. Almost a billion bacteria are needed to be ingested to cause gastroenteritis in a normal person. However, in a predisposed person, just a couple of thousands can become invasive and reach the blood or brain (93).
The primary virulence strategy of L monocytogenes is the ability to invade, survive, and replicate within various mammalian cells, such as epithelial cells, endothelial cells, hepatocytes, lymphocytes, and neurons (53). Its virulence is mainly dependent on internalins, which are surface proteins for host cell attachment; Listeriolysin O, which allows it to escape from host cell vacuoles; actin polymerization (ActA), which helps the bacteria move within and between cells; and phosphatidylinositol-specific phospholipase C (PI-PLC), which also helps escape host cell vacuoles and causes membrane disruption. It also parasitizes certain monocytes and gets transported to blood, other organs, and the brain (36).
It can neutralize host defenses, inhibit competitor bacteria, get into the gut epithelium and spread without much local inflammation, evade immune defenses, and spread to the blood, brain, and placenta, causing extensive inflammation and damage (93).
Listeria thrives when the acid in the stomach is reduced and pH goes above 3.5. It easily goes past various defenses; neutralizes bile salts and goes past the duodenum; disrupts the protective gut microbiome with Listeriolysin S, a bacteriocin (92; 52).
Once inside the intestine, internalins bind to receptors and induce uptake into vacuoles by phagocytes as well as nonphagocytic intestinal cells. Next, the vacuoles are punctured by listeriolysin O (LLO) and 2 phospholipases, and Listeria escapes into the cytoplasm (93).
Within the cytosol, Listeria hijacks various host processes to multiply rapidly and uses the host actin to develop actin tails, propel itself within the cytoplasm, break the cell membrane, and reach the adjacent cell, evading the immune system and continuing the cycle in the next cell. During this intestinal phase, everything is silent, or there is just a mild gastroenteritis (93).
Next, it enters the lymph nodes, and via the bloodstream it reaches the liver and spleen, ready to cross further barriers; the fetoplacental in pregnant women and the blood-brain barrier in immunocompromised persons.
L monocytogenes crosses the blood-brain barrier and infiltrates the CNS by 3 possible mechanisms: invasion of the endothelium of the cerebral vasculature via vacuoles as in the intestine; via infected leukocytes, the “Trojan Horse mechanism” (114); and the very peculiar and almost unique method of retrograde spread through various cranial nerves (08).
It is not fully understood how bone marrow monocytes first become infected or why these cells are susceptible to intracellular infection rather than being able to kill the bacteria (36).
There is evidence in sheep and other domestic animals, as well as pathological and radiological evidence in humans, suggesting retrograde spread of the bacterium along certain cranial nerves, particularly from injured oropharyngeal and periodontal tissue via the trigeminal nerve and from the gut mucosa via the vagus nerve (08; 113). The highly prevalent problem of dental disease may explain why the trigeminal nerve is much more frequent than the vagus. The longer incubation period of nearly one month may be explained by the longer course of the vagus (08; 113).
This invasion via nerves directly to the brainstem is seen particularly in immunocompetent individuals and in ruminants. Most humans with Listeria have impaired immunity (due to extreme age, disease, drug, or pregnancy), and it is the hematogenous route that is preferred in them (08). In one large recent series (MONALISA), only 10 (4%) of 252 patients with neurolisteriosis were younger than 40 years, had no comorbidity or ongoing pregnancy, and no report of substantial infection before listeriosis (24).
Peculiarly within the brain, Listeria seems to use its actin tail to spread along white matter tracts inside axons. Some other microbes like rabies also spread retrograde via the intra-axonal route, evading the immune system. But Listeria adds insult to injury. It attracts neutrophils and phagocytes to chase them and invade axons, leading to a track of inflammation and microabscesses. This may explain why Listeria spreads and causes progressive brain damage, despite a good intrathecal immune response (14; 46; 08; 113)
Like most meningeal infections, the bacteria do not directly affect the host but rather evoke an immune response that is responsible for morbidity and mortality. It evades and dampens the host immune responses by various ways. Following infection with L monocytogenes, innate immune responses are rapidly triggered and are essential for host survival, and it induces a robust CD8 T-cell response, which plays a critical role in resolving the infection and providing protective immunity to reinfections (93; 52).
Neonates can become infected transplacentally from maternal bacteremia. The organism can also be acquired during vaginal delivery.
• Ubiquitous distribution often contaminates certain food products.
• Humans get a few exposures per year to small numbers of bacteria.
• It is a rare disease, with the second highest case-fatality rate amongst food borne diseases
• Most cases are sporadic, despite occasional major outbreaks.
• Invasive listeriosis is reducing due to various control measures but still remains the third highest cause of CNS infections worldwide.
• In the immunosuppressed it is the second highest cause of CNS infection.
• Rhombencephalitis affects immunocompetent healthy young adults.
• It fights back control measures, for example, certain disinfectants encourage growth of more virulent subtypes.
• Persons at risk are extremes of age, pregnant women and the immunocompromised, diabetics, alcoholics, and persons with malignancy or chronic illness.
• Risky foods include dairy products, fruits, vegetables, meat products, and fish products, but even hospital foods have been implicated.
L monocytogenes is ubiquitously distributed and grows in a wide variety of environments including soil, water, plant matter, diverse food items, and intestinal tract of mammalian hosts (87). Surface contamination of meat and vegetables has been found in up to 15% samples, and humans are frequently exposed to small numbers of L monocytogenes, with up to 5 to 9 exposures per person-year. It is only when the dose is large or the host is susceptible that illness occurs (99).
According to the World Health Organization, listeriosis is a relatively rare disease, with 0.1 to 10 cases per 1 million people per year, depending on the countries and regions of the world. It is important due to its deadly nature, with the second highest case-fatality rate of the food borne illnesses and being responsible for 19% to 28% of all food-borne disease-related deaths. It has the highest hospitalization rate of 99% among the foodborne diseases (54).
In 2010, listeriosis caused an estimated 23,150 illnesses, 5463 deaths, and 172,823 disability-adjusted life-years worldwide (34).
The highest incidence of disease was found in Mexico, Central America, and the West Indies. The lowest incidence of disease was found in Eastern Europe, Caucasus, and Central Asia. Of all cases, roughly 80% were nonperinatal infections, of which 31% were CNS infection; 26% of nonperinatal cases were fatal (34).
The CDC estimates that L monocytogenes causes roughly 1600 serious infections and 260 deaths per year in the United States (98). The latest review of December 2021 remains 1600 serious infections and 260 deaths, and the annual incidence of laboratory-confirmed listeriosis in the United States is about 0.24 cases per 100,000 population (23).
The majority of cases of listeriosis are sporadic, rather than a part of an outbreak. Most sporadic cases are likely due to consumption of contaminated food. Despite all efforts by government and food agencies, L monocytogenes does cause major foodborne outbreaks globally (110; 34; 54).
Seasonal trends are seen in Europe and in the United States, with peak incidence of invasive listeriosis cases in the summer months (Mandell).
Gastroenteritis. Listeria is an uncommon cause of gastroenteritis, mainly affecting healthy children and adults in outbreaks and uncommonly as sporadic cases. Attack rates during outbreaks have ranged from 52% to 100%.
Invasive listeriosis. Invasive listeriosis has been declining due to various control measures. The incidence of invasive listeriosis decreased by 42% from 1996 to 2012 (51), and listerial meningitis cases decreased by 46% between 1998 and 2007.
Despite all this, Listeria remains one of the top 5 most common pathogens of CNS infections in the Western world; is third worldwide; and is second among patients with diabetes, with alcohol dependence, and on immunosuppressive therapies. Also, compared with other pathogens causing CNS infections, L monocytogenes mortality continues to be among the highest (104; 109; 18).
Most cases are sporadic (21). Of nonpregnant individuals who develop L monocytogenes bacteremia, 97% have at least one underlying immunodeficiency, either due to one or more medical conditions or due to immunomodulating medications (24). Similarly, only 10 (4%) of 252 patients with neurolisteriosis were younger than 40 years, had no comorbidity or ongoing pregnancy, and had no report of substantial infection before listeriosis (24).
Listeria is the third most common cause of bacterial meningitis in general, causing roughly 5% of cases overall. A large study in the Netherlands showed the causes to be S pneumoniae in 51%, N meningitidis in 37%, and L monocytogenes in 4% of cases (13). Approximately one third of listerial meningitis occurs in the newborn. In people aged 50 years or more, the percentage of Listeria goes up to 9% (89).
When considering causes of meningitis in immunocompromised persons, Listeria is the second commonest cause. These are patients on immunosuppressive medications or long-term steroids, or who have solid organ tumors, lymphomas, or an organ transplant (108). In infants, E coli, S agalactiae, and L monocytogenes are the most common causes of bacterial meningitis (02).
Approximately one third of listerial meningitis occurs in the newborn.
Rhombencephalitis is probably underrecognized but still reported in 9% to 17% of CNS Listeria cases (09; 24). In contrast to other forms of listerial infection, rhombencephalitis strikes healthy adults; only about 8% are immunocompromised (05). In a literature review of 120 patients, age ranged from 14 to 87 years, with 16 patients less than or equal to 29 years old, 59.3% of the patients were men. Of the 96 patients whose immune status was known, 69.8% (n = 67) were immunocompetent (57).
Rhombencephalitis caused by L monocytogenes developed in a patient without severe lymphocytopenia who was treated with dimethyl fumarate (97).
Cerebritis and abscess formation occur in about 1% of patients with listeriosis. Immunosuppression is the major risk factor. Men are more often affected than women with a ratio of 6:1.
Biodiversity of Listeria. L monocytogenes is a highly heterogeneous species; it can be divided into 4 evolutionary lineages, 13 serotypes, and 4 PCR serogroups. The above categories are further subdivided into clones, which are geographically and temporally widespread (73).
The vast majority of human listeriosis cases are caused by three serotypes: 1/2a, 1/2b, and 4b (31). 1/2a and 1/2b are responsible for most cases of febrile gastroenteritis, whereas serotype 4b more commonly causes invasive diseases (70).
There are various clones leading to tremendous diversity in virulence, geographical distribution, etc. Certain clones are most likely to cause disease, certain infect dairy products, certain affect meat, and certain tend to cause rhombencephalitis. The genotype clonal complex CC6 or ST6 has resistance to benzalkonium in disinfectants and so tends to grow preferentially and has become the major cause of Listeria meningitis in the Netherlands (61; 62; 73; 74).
Patient groups at risk. Most cases are sporadic. Most normal and healthy persons do not get infection on exposure and even if they do, it is usually a self-limited gastroenteritis.
Around 4% of otherwise healthy young (less than 40 years age) persons can get invasive disease without any identifiable risk factors like age, immunocompromised state, or pregnancy (24). It is possible that they have genetic susceptibility or are exposed to a higher bacterial inoculum.
Persons at risk of invasive disease include elderly and infants, pregnant women, and persons with a compromised immune system. Extremes of age are a risk with both neonates and elderly being at risk. Old age is itself a risk. Incidence in persons over 75 years of age is nearly 20 times greater (0.98 cases out of 100,000) than in individuals younger than age 65 years (0.05 cases out of 100,000) (43).
Pregnant women have a 17 times higher risk of getting listeriosis than the general population. Pregnancy accounts for almost one sixth of all invasive listeriosis cases (30). Pregnant Hispanic women and low socioeconomic status have been identified as high-risk groups (101; 83).
Of nonpregnant individuals who develop L monocytogenes bacteremia, 97% have at least one underlying immunodeficiency, either due to one or more medical conditions or due to immunomodulating medications (24). These conditions include solid-organ and hematologic malignancy, kidney disease, cirrhosis, diabetes mellitus, giant cell arteritis, organ transplantation, AIDS, chronic corticosteroids, or other immunosuppressants, including tumor necrosis factor-alpha antagonists (78; 64; 91).
In the Monalisa study, in patients with bacteremia or neurolisteriosis, the predisposing immunosuppressive condition was solid organ cancer in 209 (31%) out of 679 patients, and underlying cancer was revealed in 18 (3%) of 679 patients.
Therefore, almost one-third of cases of invasive listeriosis were seen in patients with cancer, and in 3% underlying cancer was revealed after the diagnosis of invasive listeriosis (24).
L monocytogenes meningitis has been reported in multiple sclerosis patients treated with alemtuzumab (94) and rhombencephalitis with dimethyl fumarate (97).
Proton pump inhibitors increase the risk of developing invasive infection (50).
All above categories of patients at risk should be warned about dietary practices and precautions for Listeriosis, for example, patients on dimethyl fumarate (97).
Foods at risk. Listeriosis has been documented to occur from various foods, but the highest risks are from delicatessen-style ready to serve meats and unpasteurized cheeses.
The commonest offenders are dairy products (eg, ice creams, cheeses, butter), fruits and vegetables, meat products, and fish products (99). Even hospital foods like sandwiches have been implicated (101).
Due to their eating preferences, 2 groups of elderly persons were identified to be at highest relative risk: one who gave preference to fruits, vegetables, and cheeses; and the other to cereals, milk, and yogurt (112).
Tracking listeriosis cases and linking to food products is now done by pulsed field gel electrophoresis and whole-genome sequencing, which have largely replaced older methods such as serotyping (31).
• Awareness, regulation, and testing at the food-processing level are very important.
• Some precautions need to be taken by everyone, as for preventing any food-borne illnesses.
• Persons at high risk include elderly, pregnant women, infants, and anyone with a compromised immune system for any reason.
• Those at high risk need to be educated about their risk, and precautions need to be taken about food choice and food handling.
• Trimethoprim-sulfamethoxazole prophylaxis effectively prevents listeriosis in high risk patients, for example those with HIV.
• Patients do not need to be isolated.
• A healthy gut microbiome may be protective.
• On possible exposure to Listeria contaminated food, persons who are asymptomatic do not need treatment but need to keep a watch for 2 months for fever or muscle aches or fatigue, especially the high-risk category.
Steps at food processing level. L monocytogenes can contaminate and flourish in the seemingly safe food processing environment due to its ability to endure various stresses, such as sanitizers, low pH, and cold temperature, and its ability to form biofilms. This contamination of food products is particularly important for ready-to-eat foods, as there is no antimicrobial step between production and consumption (54; Rogalla and Bomar 2021).
Guidelines have promoted universal awareness of the problem in the food-processing industry, which has undertaken hazard analysis at critical control points and microbial risk assessment programs to reduce contamination of foods with L monocytogenes and other pathogens.
A debate continues between zero tolerance advocates and those supporting a risk-assessment approach to Listeria contamination of food (35). The U.S. Food and Drug Administration has a zero tolerance policy for L monocytogenes in its industry sampling programs, whereas other countries allow a small amount of contamination, in an attempt to balance protection of public health and wastage of otherwise edible food (99).
Sophisticated surveillance and reporting systems have also helped to rapidly identify sources and recall and take other measures to stop spread once there is an outbreak or an infection.
There are various ongoing efforts to try and avoid contamination of foods and food processing environments due to the high risk to the consumer as well as inconvenience and cost of food recall. General measures to be taken by everyone.
These recommendations help to prevent any foodborne illness and include:
• Proper washing and handling food
- Thoroughly cook raw food from animal sources
- Thoroughly wash, scrub if needed, and dry raw vegetables and produce like cucumbers and melons
• Food choices
- Use precooked or ready-to-eat food as soon as possible and do not store beyond the expiry date
- Use leftovers within 3 to 4 days
- Avoid raw (unpasteurized) milk or foods made from raw milk
• Keep kitchen safe
- Wash hands, knives, and cutting boards after handling uncooked foods
- Keep refrigerator free of spills and temperature below 40°F and freezer below 0°F
Special precautions for high risk individuals. People at high risk, which include immunocompromised persons due to various diseases or drugs, pregnant women, elderly, and infants need to be educated about listeria and about foods that are at risk of being contaminated with listeria. Recognition and education of subset populations at even higher risk such as pregnant Hispanic women in the United States should be prioritized (40). Similarly, elderly persons need to be educated about paying attention to the following food habits.
They should consider the following (40):
- Avoid soft cheeses and Mexican-style cheese
• Meats and seafood
- Avoid from delicatessen counters unless thoroughly reheated or steaming hot before eating
- Avoid refrigerated meats and seafood unless thoroughly cooked again
- Separate raw meat and poultry from ready-to-eat food
- Wash hands properly before and after handling
- Scrub surface and dry melons properly and sanitize the brush after each use
- Consume melon immediately after cutting or refrigerate promptly and eat within a week
- Discard cut melons left at room temperature for more than 4 hours
• Raw sprouts
- Do not eat any kind of raw sprouts and inform when eating out
- Cooking sprouts thoroughly can reduce the risk
Listeriosis is effectively prevented by trimethoprim-sulfamethoxazole given as Pneumocystis prophylaxis to organ transplant recipients, those receiving corticosteroid immunosuppression, or individuals infected with human immunodeficiency virus.
Second episodes of neonatal listerial infection are virtually unheard of, and intrapartum antibiotics are not recommended for women with a history of perinatal listeriosis. Except for transmission from infected mother to fetus, human-to-human transmission of listeriosis does not occur; patients do not need to be isolated.
Role of the gut microbiome. Despite frequent exposure, very few persons actually get Listeriosis, and a healthy gut microbiome probably plays the key role in protecting against Listeriosis. Studies suggest that it may be possible to enhance this protection by promoting healthy bacteria, for example, by using probiotics (10). If proven, this could be a simple strategy for augmenting prevention in individuals deemed to be at high risk apart from paying attention to food habits as explained above.
Recommendations for possible exposure to Listeria-contaminated food. On possible exposure to food, which is known to be contaminated with Listeria, for example, during an outbreak, certain steps need to be taken depending on the person’s risk category and symptoms.
Most normal and healthy persons will either not get any illness or may get a self-limited gastroenteritis. They do not need any tests or any specific treatment. They should be counselled and monitored for 2 months, watching for any fever, muscle ache, headache, or fatigue. This is particularly important in the high-risk category: the elderly, pregnant, or immunocompromised.
In the high-risk category, if there is fever, it is advised to get blood cultures done and start intravenous ampicillin. If diagnosis is proven, treatment should be continued for 2 weeks. Adding gentamicin is controversial. Most authorities recommend trimethoprim with sulfamethoxazole if there is allergy to ampicillin (28).
In the high-risk category, if they have mild symptoms without fever, one may still consider sending blood cultures and observing very closely. More information is found at the following site:www.cdc.gov.
We need to keep a high index of suspicion for listeriosis and even start empirical treatment until the disease is ruled out, in view of the possibility of rapid worsening and high mortality and morbidity (99).
It should be suspected in the following clinical scenarios, especially if the patient has recently ingested milk, soft cheeses, or cold deli meats or hot dogs.
• Meningitis or parenchymal brain infection in persons greater than or equal to 50 years of age with hematologic malignancy, solid-organ malignancy, organ transplant, or AIDS or on immunosuppressive therapies
• When the meningitis is subacute or there is concomitant affection of the brain parenchyma
• Subcortical brain abscesses
• A young healthy person presenting with an acute brainstem disorder within days or weeks of having eaten “risky” food, even in the absence of fever or headache
Listeriosis should also be thought of in every neonate with respiratory distress, sepsis, or meningitis; in fever during pregnancy, especially in the third trimester; and in foodborne outbreaks of febrile gastroenteritis with negative stool cultures (52; 99; Rogalla and Bomar 2021).
Meningitis and meningoencephalitis. Rather than a pure meningitis, a meningoencephalitis or combination of simultaneous meningeal and brain parenchyma infection is more common with listeriosis than in other forms of bacterial meningitis (69; 71; 24).
On the basis of the clinical presentation or CSF picture, Listeria meningitis is indistinguishable from that due to more common bacterial pathogens, though it may be more subacute (90). The chances of Listeria being the cause is higher in the elderly and in neonates (89; 02). Diagnosing meningitis in the elderly may be difficult, as they may have nonspecific confusion without any fever, headache, or nuchal rigidity. Up to one third of the normal elderly may seem to have a stiff neck (32).
Patients with a prior history of receiving immunosuppressive therapy within 1 month and chronic liver disease have 8.1-fold and 5-fold increased risk of meningitis by L monocytogenes compared to S pneumoniae, respectively (68).
Listeria meningitis can be mistaken for viral, tubercular, fungal, or syphilitic meningitis and in patients with cancer, for leptomeningeal carcinomatosis (01).
Listeria abscess or abscesses. Subcortical abscess caused by L monocytogenes should be added to the list of more frequently occurring polymicrobial, streptococcal, and staphylococcal brain abscesses, particularly in the immunosuppressed or with simultaneous meningitis.
The abscesses tend to spread along white matter tracts, creating a characteristic worm-like enhancing MRI lesions.
Listeria rhombencephalitis. This must be considered in any acute or subacute brainstem lesion, especially if fever and/or consumption of risky food, even in normal and young persons, even if not much systemic signs and gross CSF abnormalities (33; 99).
The most common cause of rhombencephalitis is Listeriosis, but it has a number of differentials, including other infections like enterovirus 71, the various herpes viruses, autoimmune diseases like Behcet disease, and less commonly, lupus, relapsing polychondritis, and paraneoplastic syndromes, especially with anti-Yo, anti-Tr, anti-Hu, anti-Ri, anti-Ma, and anti-amphiphysin antibodies, with underlying small cell lung cancer. It can be mistaken for and even occur in persons with demyelinating CNS diseases, such as multiple sclerosis or neuromyelitis optica. Other disorders to be kept in mind are intra-axial brainstem tumors, strokes, central pontine myelinolysis, and CLIPPERS (56; 27; 113).
Some pointers may help in narrowing down the causes:
• Cerebellar ataxia common in infectious and paraneoplastic syndromes.
• Long tract signs are common with Behcet disease and Listeria, but not other infections.
• Altered consciousness in infectious cases and some types of Behcet disease.
• Fever is common with infections and Behcet disease.
• Meningismus in infections.
The MRI is also very helpful, and an abnormal MRI is a must in Listeria rhombencephalus, multiple sclerosis, and Behcet disease, whereas a normal MRI is highly suggestive of paraneoplastic or possibly viral (56; 79; 20).
• CSF abnormalities are characteristic of pyogenic meningitis but may also mimic viral, tuberculous, or fungal meningitis.
• MRI is abnormal in almost 90%, usually nonspecific, but sometimes it might be characteristic as in rhombencephalitis or worm-like brain abscesses.
• A normal MRI does not rule out CNS Listeriosis.
• Culture from CSF or blood is the mainstay of diagnosis, but it takes time.
• PCR is faster and may be positive, even in partially treated cases.
• Serological testing and stool culture are not useful in individual cases.
Hemogram. The peripheral blood usually shows polymorphonuclear leukocytosis and lymphopenia, especially in the nonperinatal cases. Despite its name, L monocytogenes infections rarely produce a monocytosis in humans (24).
CSF findings. CSF usually shows a pleocytosis around 500 to 600 with neutrophil predominance and often (but not always) low glucose (81; 17; 24).
Only one third of cases showed listeria on gram stain (81; 24). Caution is needed because it may appear as gram negative or look like short rods or elliptical cocci; therefore, it may be mistaken for diphtheroids, streptococci, H influenzae, enterococci, or enteric bacteria (19).
MRI. MRI has clear advantages to CT (06). It shows various combinations of neuroradiological findings, none being specific. In one study of 71 cases, MRI was abnormal in 87%. Meningeal enhancement was seen in 35%, abscesses or nodular lesions in 14%, and contrast-enhancing ventricles or hydrocephalus in 10%.
CNS listeriosis is often thought to involve the brainstem, and hemorrhage is not usually expected. In fact, brainstem involvement narrows down the differential diagnosis and is more specific, but only about 10 % cases of CNS listeriosis show these radiological signs of rhombencephalitis. Somewhat unexpectedly, hemorrhagic lesions are frequent (15 %).
This brings us to a clinical pearl: one may start empirical anti-listeria therapy when neurolisteriosis is suspected, even when MRI does not show rhombencephalitis, brain abscess, or meningeal-enhancement (25).
Listeria monocytogenes abscesses frequently present as markedly irregular formations, revealing characteristic worm-like tubular pattern of chaotic curvilinear arrangement. This “tunnel sign” or “worm-like sign” can be considered very typical.
Listeria monocytogenes should be remembered in cases wherein brainstem or cerebellar involvement is detected on cranial MRI, particularly abscess or contrast enhancement (06). Almost all cases of Listeria rhombencephalitis have an abnormal MRI (56; 79; 20).
Culture of CSF or blood. CSF culture reveals the organism in 5 out of 6 cases, whereas blood cultures are positive in more than half of patients. One in 6 may show a positive blood culture in the absence of a positive CSF culture. In the appropriate clinical setting, neurolisteriosis may be diagnosed with positive blood cultures alone (24). Cultures may be negative if patients received empirical antimicrobial treatment before sample collection.
PCR. A real-time PCR assay has demonstrated high sensitivity and specificity for CNS listeriosis, even where CSF culture was negative, for example, due to previous treatment. It is rapid and reliable. This real-time quantitative PCR has sometimes been used to monitor therapy and detect bacterial persistence, for example, in ventriculo-peritoneal shunts (67). Multiplex PCR testing for CSF for an array of viruses, bacteria including L monocytogenes, and fungi is now commercially available (The BioFire® FilmArray® Meningitis/Encephalitis Panel).
It should be noted that in one series of listerial rhombencephalitis cases, 22% did not have an elevated CSF cell count. Moreover, the sensitivity of CSF culture is lower in rhombencephalitis, where only 41% and 61% of reported patients had positive CSF and blood cultures, respectively (05). PCR might prove useful in such culture negative cases (86).
• Prompt and appropriate antibiotics are the key.
• A delay by even a few hours can be fatal.
• The therapy of choice is ampicillin or benzylpenicillin combined with an aminoglycoside or TMP-SMX.
• Only if both penicillin and TMP-SMX are contraindicated may one try meropenem plus gentamicin.
• Cephalosporins do not work.
• The duration of therapy should be at least 3 to 4 weeks in immunocompetent and 6 to 8 weeks in immunosuppressed persons.
• Steroids are probably deleterious and should not be used.
Antibiotic therapy is the mainstay of Listeria treatment. Delay, even by a few hours, can lead to increased mortality or morbidity (07; 68).
We need to keep in mind the following facts (48; 63; 12):
• Most antibiotics have only bacteriostatic activity against listeria.
• Only a few can reach the intracellular environment of listeria.
• For CNS listeriosis the antibiotic also has to be able to cross the blood brain barrier.
• Listeria can form subpopulations of dormant, antibiotic-tolerant persisters.
There are no controlled clinical head to head trials for the choice of antibiotic therapy in Listeria infection; therefore, the data are mainly based on observational and in vitro studies.
For example, the large MONALISA study in France showed a beta-lactam like amoxicillin or an aminoglycoside were each associated with reduced 3-month mortality on multivariate analysis compared with regimens that did not include each of those agents.
Penicillin/ampicillin. Penicillin, amoxicillin, and ampicillin work well because in addition to reaching inside the CSF and the intracellular environment, they are able to bind to penicillin-binding protein 3 (PBP-3) of Listeria and cause it to die (103; 90). However, penicillins are mainly bacteriostatic at the concentrations reached and so need to be combined with another bactericidal drug.
The dose recommended in adults is ampicillin 2 g intravenously every 4 hours or penicillin G 4 million units intravenously every 4 hours.
Infants and children also are treated similarly with ampicillin and gentamicin. In general, the dose is higher if there is either proven or possible CNS Listeriosis. If CNS listeriosis has not been ruled out, the dose of ampicillin is 300 mg/kg/day in 4 divided doses for babies from birth till age 60 days is recommended. In the first week they are given in 3 divided doses. In infants and children after the age of 60 days, the dose is increased to 300 to 400 mg/kg/day in 4 to 6 divided doses, with a maximum of 12 g per day.
If CNS infection has been ruled out, the dose of ampicillin advised in the first week of life is 100 mg/kg per day intravenous in 2 divided doses for those with weight less than or equal to 2 kg or 150 mg/kg per day intravenous in 3 divided doses for infants with weight greater than 2 kg. Between 8 to 28 days, the dose is 150 mg/kg/day divided in 3 doses. After the age of 29 days, the dose is 200 mg/kg/day intravenous in 4 divided doses, up to a maximum of 8 g per day (40).
Gentamycin. Ampicillin and penicillin G demonstrate delayed in vitro bactericidal activity at concentrations attainable in the cerebrospinal fluid (CSF). Despite its poor CNS penetration (77; 07), gentamicin, which is bactericidal, enhances the killing rate with ampicillin in vitro (81; 90).
Amoxicillin-aminoglycoside combination therapy longer than 3 days had an independent protective effect on survival compared with no combination therapy (80% vs. 20%; OR 0.35, 95% CI 0.22-0.56) (24).
The combination of ampicillin with gentamycin is recommended by the European guidelines and even considered the treatment of choice by some authorities (40) The downside of gentamicin is nephrotoxicity and ototoxicity; therefore, patients should be monitored for nephrotoxicity and ototoxicity (105; 107). Also, it cannot be used in persons whose renal function is already impaired. Gentamicin is advised in adults with normal renal function in a dose of 5 mg/kg per day intravenous in 3 divided doses. In infants, gentamicin is advised along with the ampicillin until the infant is clinically improved and the CSF is sterile, whereas ampicillin is given for 14 to 21 days.
For infants less than 60 days old, depending on the gestational and postnatal age, the dose of gentamicin is follows:
• Gestational age less than 30 weeks:
- Postnatal age less than or equal to 14 days: 5 mg/kg intravenous every 48 hours
- Postnatal age greater than 14 days: 5 mg/kg intravenous every 36 hours
• Gestational age 30 to 34 weeks:
- Postnatal age less than or equal to 10 days: 5 mg/kg intravenous every 36 hours
- Postnatal age greater than 10 to 60 days: 5 mg/kg intravenous every 24 to 36 hours
• Gestational age greater than or equal to 35 weeks:
- Postnatal age less than or equal to 7 days: 4 mg/kg intravenous every 24 hours
- Postnatal age greater than 7 to 60 days: 5 mg/kg intravenous every 24 hours
For infants and children greater than 60 days of age, the dose advised is 7.5 mg/kg per day intravenous in 3 divided doses.
Trimethoprim-sulfamethoxazole (TMP-SMX). TMP-SMX is associated with a favorable outcome, probably due to good CNS penetration (90). Regimens with TMP-SMX were associated with reduced 3-month mortality (OR 0.49, 95% CI 0.26-0.92) compared to regimens without TMP-SMX (24).
TMP-SMX plus ampicillin is the choice when gentamicin cannot be used because of impaired renal function or concomitant use of nephrotoxic drugs. In fact, a small study of 22 patients suggested this combination may be more effective than ampicillin plus gentamicin (76).
In penicillin-allergic patients, TMP-SMX plus gentamicin combination is advisable. The dose advised is 15 to 20 mg/kg intravenous per day of the trimethoprim component divided into 4 daily doses.
Meropenem. Meropenem has excellent in vitro activity against Listeria and has been used successfully to treat listeriosis. However, there are reported failures, and a retrospective study showed a higher mortality compared to penicillin (105).
Therefore, only when both penicillin nor TMP-SMX cannot be used, may one use the combination of meropenem with gentamicin.
The dose of meropenem is 2 g intravenously every 8 hours in adults, and 120 mg/kg per day in 3 divided doses in children; the maximum dose is 6 g/day (40).
Other second-line drugs. Quinolones have an excellent tissue and cell penetration and are rapidly bactericidal for Listeria, but their clinical activity is not as high as expected. Newer quinolones may have a role, but it has yet to be elucidated.
Linezolid and rifampicin seem useful on the basis of experimental studies, but there are not much clinical data (90).
Antibiotic agents to avoid. Certain antibiotics are suboptimally effective against Listeria and should, therefore, be avoided (80; 40).
• Vancomycin has been used as an alternative agent, but failures have been reported. It may be used in pregnant patients when other agents cannot be used.
• Erythromycin and tetracyclines are bacteriostatic, their clinical efficacy is uncertain, and resistance has been reported.
• Chloramphenicol is less effective and should be avoided.
• Cephalosporins are inactive in vitro and ineffective clinically.
Duration of treatment. There are no definitive answers on the duration of therapy; therefore, one may decide based on the seriousness of the illness and on the status of the patient, whether immunocompetent, healthy and young, or otherwise. Response to therapy may be used to monitor clinical response, serial brain imaging, and possibly quantitative PCR or even CSF culture to confirm eradication in CSF (67; 40).
For immunocompetent patients with CNS disease at least 3 to 4 weeks of treatment is recommended (107; 40).
Immunocompromised patients have had recurrences after 2 weeks of treatment (70), so 4 to 8 weeks of therapy is suggested for CNS infections in this group (05; 69; 70; 81).
Cerebritis or brain abscesses are advised with longer treatment, for at least 6 to 8 weeks (69; 81).
Gentamicin is generally continued until the patient improves (usually 7 to 14 days) or, in poor responders, for up to 3 weeks if there is no nephrotoxicity or ototoxicity (40).
Steroids. Steroid therapy is associated with increased mortality in patients with neurolisteriosis. They are useful as adjunctive treatment for bacterial meningitis due to S pneumoniae but should be stopped once L monocytogenes is identified as the causative pathogen (24).
• Untreated meningoencephalitis or rhombencephalitis has almost 100% mortality.
• Mortality depends on immune status, site of infection, and how early or late diagnosis and appropriate therapy are initiated.
• Mortality is 45% with bacteremia and 30% with CNS listeriosis.
• Mortality is higher in those who received steroids.
• CNS infection is an important risk factor for mortality and morbidity.
• Adults with no underlying disease almost always do well.
• Older patients with listeria meningitis may need to be screened for cancer.
• Outcomes for pregnant patients with listeria are typically good.
• Fetal and neonatal infections can be severe, leading to fetal loss, preterm labor, neonatal sepsis, meningitis, and death.
• Listeriosis has a specific tropism for the placenta.
• It can reach and silently and efficiently invade the placenta and induce devastating consequences on the developing fetus.
• Pregnant women are particularly prone to listeriosis with an estimated 17-fold increase in incidence (10 to 100 times).
• Almost all infected women transmit Listeria to the fetus within 2 weeks, quite often without much signs or symptoms themselves.
• One in 7 cases of listeriosis occurs in pregnant women.
• It causes a minor illness often mistaken for a urinary tract infection or a flu-like viral infection.
• Only 5% pregnant women with maternal listeriosis experience uneventful subsequent pregnancy and delivery.
• Fetal infection has serious implications with fetal loss in about 20% and newborn death in about 8% of cases.
• Neonatal listeriosis can manifest in 3 forms: early-onset sepsis syndrome, late-onset meningitis, and, the rarer granulomatosis infantiseptica.
• Most pregnant women are not aware of listeriosis and precautions to be taken, and there is a need to educate them.
• There needs to be a low index of suspicion for maternal listeriosis and a low threshold to begin treatment in women with suspected infection.
Maternal listeriosis. One in 7 cases of listeriosis occurs in pregnant women. Compared with nonpregnant females, the risk is increased between 10 to 100 times higher according to rough estimates (26), and almost 17-fold by most authorities (30). The hypervirulent strains belonging to clonal complexes 1, 4, and 6 are the most associated to maternal-neonatal infections (26).
Possibly due to dietary habits, there is an even higher incidence of pregnancy associated listeriosis in certain ethnic minorities, for example, American Hispanic women in the United States compared to the general population (30.0% vs. 3.5%, respectively) (30). This difference may be explained by less awareness of preventive measures or less readily available access to medical care, or both factors (26). Women with twin or triplet pregnancies are at higher risk of infection (72).
Unlike other invasive listerial infection, listeriosis in pregnancy mainly affects otherwise healthy women. The cause is thought to be the physiologic suppression of immunity, which is maximum in the third trimester and is necessary to avoid rejection of the fetus by the body’s immune system. This has the unwanted side-effect of increased susceptibility to intracellular pathogens such as L monocytogenes, Coxiella burnetii, and Toxoplasma gondii (30).
Despite invading the bloodstream, listeriosis in pregnancy presents as a relatively mild illness with nonspecific or subtle symptoms like mild fever (in 12% to 85%) and myalgia. It may be mistaken for a flu or a urinary tract infection (69; 82; 39; 24; 30). There may just be nonspecific obstetrical signs or fetal loss.
Pregnant women do not usually get severe disseminated disease or CNS listeriosis (82), unless there are other risk factors causing immunosuppression like a splenectomy, HIV infection, steroid use, diabetes, or use of immunosuppressive medications (49). It is not necessary to do CSF assessment routinely in maternal listeriosis (26).
There is often a delay in diagnosis: median time of 4.8 days in one study (65). Despite this frequent delay in diagnosis, maternal morbidity and mortality are rare, and almost all recover, sometimes even without treatment (24). Maternal mortality rate is 0%, compared to 30% and 46% for neurolisteriosis and bacteremia, respectively (24).
This benign maternal course contrasts with the dubious distinction of being one of the infections associated with the highest fetal and neonatal morbidity.
Despite being such a dangerous problem for pregnant women, most pregnant women are not aware of it. A national survey of 403 pregnant women from the United States found that only 18% were familiar with listeriosis, and less than 30% of those knew how to prevent ingesting contaminated foods (30).
Fetal and neonatal listeriosis. Despite not having many signs or symptoms themselves, almost all women (96%) with maternal Listeria transmit the infection to the fetus (30).
L monocytogenes is able to invade the placenta, get past the fetoplacental barrier, and infect the fetus, causing chorioamnionitis, spontaneous abortion, stillbirth, preterm labor, and neonatal infection in the majority (30). There is no specific information about teratogenicity (30).
Fetal loss is more common (between 20% to 30%) than neonatal death (8%) (42). In the MONALISA study of 107 pregnant women with listeriosis, only 5 did not experience some adverse outcome. Ten neonates (12%) had normal physical examinations without signs of infection at birth, and subsequently, 6 of these 10 neonates went on to develop late-onset disease (24).
The earlier in gestation the infection, the worse the outcome. The risk of miscarriage is 65% for infection in the first trimester as compared to 26% in the second or third trimester (22). Another series of 166 cases acquired in the first, second, and third trimesters documented fetal survival at 0%, 29.2%, and 95.3%, respectively (39). In the MONALISA study, all fetal losses occurred when the infection was acquired prior to 29 weeks (24).
Listeriosis has been one of the top causes of severe bacterial infection in the neonatal period, but in recent decades, there has been a reduction, possibly due to improved food safety and antenatal screening and prophylaxis with penicillin or amoxicillin for group B Streptococcus (66).
Neonatal listeriosis can manifest in 3 forms: granulomatosis infantiseptica, early-onset sepsis syndrome, and late-onset meningitis syndrome (69).
Granulomatosis infantiseptica and early-onset listeriosis are acquired by transplacental infection in utero, leading to the delivery of an often premature and severely ill infant.
Granulomatosis infantiseptica is a rare, rapidly fatal disseminated infection in utero presenting at birth with widespread microabscesses and granulomas within the liver, spleen, and sometimes, skin.
Early-onset listeriosis presents mainly as sepsis in a neonate (days 1 to 7) and has a high mortality rate. It presents with pneumonia, respiratory distress, and fever. Neurologic involvement like meningitis is less common (24%).
As against the sick and premature infant born to a woman with symptoms in early-onset listeriosis, the late-onset variety leads to a healthy infant born to an apparently healthy woman. The infant is usually term and healthy at delivery, and the mother is often just an asymptomatic gastrointestinal carrier of L monocytogenes without sepsis. Infection is picked up by the infant in the colonized birth canal or later by aspiration or swallowing. Such infants present 7 to 14 days later with meningitis, in almost 94%, with fever and irritability. Thus, CNS involvement is the predominant clinical syndrome in late-onset listeriosis. The mortality rates are significantly lower as compared to the ones with early-onset neonatal infection (82).
Management of maternal listeriosis. There are no randomized trials of antibiotic treatment, and most data are based on reports of clinical experience. The diagnosis of listeriosis in pregnancy is particularly difficult, as up to 30% of infected mothers are asymptomatic. There are no rapid confirmatory tests, and placental or maternal blood cultures have a low sensitivity. When listeriosis is suspected, the recommendation is to start treatment prior to confirmation of diagnosis (30).
When a pregnant woman has a presumptive exposure, for example, having eaten food known to be contaminated or having a risk of being contaminated, the approach depends on the clinical presentation:
• If asymptomatic, no treatment nor fetal surveillance is warranted. They should be advised to return if symptoms develop.
• If there is unexplained fever greater than or equal to 38.1°C, empiric antibiotic therapy (ampicillin 2 g intravenously every 4 hours) should be initiated while diagnostic studies are pending. If blood cultures become positive, further management is discussed below. If blood cultures are negative, some authorities give a 7-day course of oral amoxicillin or oral TMP-SMX. TMP-SMX is to be avoided in the first trimester. Fetal surveillance also may be prudent.
• With mild symptoms but without fever greater than or equal to 38.1°C (100.6°F), some suggest empiric oral amoxicillin or TMP-SMX, unless blood culture comes positive.
• If blood culture comes positive in any of the above categories, they should be treated as Listeria bacteremia as usual with intravenous ampicillin or penicillin for 14 days. Gentamicin is not preferred in pregnancy. As with Listeria infection in nonpregnant persons, penicillin-allergic patients may be given TMP-SMX, except during the first trimester. In those who cannot take TMP-SMX, meropenem or vancomycin may be appropriate (28; 40).
A website on Listeria is available for pregnant women and can be accessed at the following site: USDA fact sheet.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Sudhir Kothari MD
Dr. Kothari of Poona Hospital and Research Centre has no relevant financial relationships to disclose.See Profile
Christina M Marra MD
Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.See Profile
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